In the pharmaceutical industry, high purity reactants are generally required as starting materials for producing drugs for treating individuals inflicted with a specific disease. Typically, it is required that the high purity reactants have little or no detectable amounts of impurities present therein since impurities, even if present in minor amounts, can carry over to the final product being produced. Thus, the presence of even trace amounts of impurities in the reactants is undesirable since they may adversely effect the final product or, in extreme cases, cause side-reactions to the patient to whom the drug is being administered.
One area wherein highly pure chiral reactants are sought is in developing new and improved drugs containing a benzimidazole riboside compound. This compound is currently being used for treating various human disorders such as HIV. In order to produce benzimidazole riboside compounds of high quality and quantity, highly pure L-ribose crystals are required as a reactant.
Although the prior art contains myriads of processes of producing ribose (D- or L-form), those prior art processes, including those described hereinbelow, do not form L-ribose crystals of sufficient purity which allows for the production of high purity benzimidazole riboside compounds.
In the prior art, D-ribose has been generally prepared industrially by a process in which D-glucose is oxidized with oxygen in an aqueous alkali solution to form D-arabonic acid which is isolated in the form of a metal salt, e.g., the mercurial zinc salt, and epimerized and lactonized to give D-ribonolactone; the latter is thereafter reduced with sodium amalgam to D-ribose. Heating D-arabonic acid in an aqueous alkali solution gives a mixture in which the equilibrium ratio of D-arabonic acid to D-ribonic acid is 70:30. In this prior art procedure, it is impossible to obtain a mixture containing more than 30% of D-ribonic acid. Moreover, large amounts of mercury, which present difficulties in the process, are required to form the amalgam.
Bilik et al. reported that various saccharides could be epimerized in an aqueous solution in the presence of a molybdic acid catalyst, including the epimerization of L-arabinose to L-ribose (see, for instance, Czechoslovak Pat. No. 149,472; Chemical Abstracts 81, 78 189 K).
On the basis of this knowledge, a process was developed in which D-gluconic acid was oxidized to D-arabinose instead of D-arabonic acid. Hypochlorite was used as the oxidizing agent. D-arabinose was then epimerized in an aqueous solution in the presence of a molybdenum catalyst to give D-ribose (cf. Japanese Preliminary Published Application No. 164,699 1980 and European Pat. No. 20,959 and U.S. Pat. No. 4,355,158). This process achieves an epimerization ratio (proportion of ribose in an equilibrium mixture) of only about 25%. Nevertheless, this process is superior to the one described above, since no mercury is used and fewer steps are required. In one version of the process, a major part of the arabinose is isolated in crystalline form and recycled to the epimerization reaction. To facilitate separation of the molybdic acid from the epimerization solution, the use of a molybdic acid-carrying ion exchanger resin instead of molybdic acid (cf. Japanese Patent Publication No. 40 700/1981) or the use of a molybdic acid-carrying ion exchanger fiber (cf. Japanese Preliminary Published Application No. 76 894/1980) has been described. The epimerization ratio of D-arabinose to D-ribose is 69.4:30.6. Japanese Preliminary Published Application No. 54 197/1982 discloses an epimerization ratio of 27.2% of D-ribose.
It is also known that, by heating L-arabinose in dimethylformamide in the presence of dioxobis-(2,4-pentadionate-0,0')-molybdenum (VI), 36% of the L-arabinose is epimerized to L-ribose (cf. Abe et al., Chemical and Pharmaceutical Bulletin, 28 (1980), 1324).
Further improvement in the ribose selectivity is achieved by adding boron compounds in a 2 to 3-fold molar amount to the epimerization mixture (cf. JP-OS No. 1,890,976/83, JP-OS No. 223,187/83 and German Laid-Open Application No. DOS 3,437,571). This gives an epimerization equilibrium of about 60% in aqueous solutions and up to 94% in nonaqueous solutions. The disadvantage of this process is that the boric acid cannot be separated to an extent acceptable for vitamin B.sub.2 preparation without ribose and arabinose also being removed, i.e. the yield of total sugars decreases sharply with each measure to separate the boric acid. Moreover, the unconverted arabinose in the boric acid-containing solution cannot be separated from ribose and reused.
Other references which disclose alternative methods for producing D-ribose from D-arabinose are described in U.S. Pat. Nos. 4,778,531 and 5,015,296. In the '531 patent, the epimerization of D-arabinose to D-ribose is carried out in an aqueous solution in the presence of a Mo(IV) compound and a metal salt of the formula MeX.sub.2, wherein Me is Mg, Ca, Sr, Ba or Zn and X is Cl or Br. In regard to the '296 patent, the epimerization reaction is carried out in the presence of a basic cation exchanger that is charged with a Mo(IV) compound.
Despite the current state of the art, there is a continued need to develop a new and improved process which can efficiently and continuously produce high purity L-ribose crystals starting from a solution of L-arabinose. This is especially so in the pharmaceutical industry wherein highly pure L-ribose crystals are needed as a starting material for producing, for example, antiviral drugs. In particular, highly pure L-ribose crystals, having no chiral impurities, are being sought as a starting material for producing benzimidazole riboside compounds. Such benzimidazole riboside compounds have recently been reported as an effective inhibitor of cytomegalovirus DNA synthesis without exhibiting any significant side effects in patients treated with the benzimidazole riboside compound. As is known to those skilled in HIV research, the cytomegalovirus causes blindness in HIV effected patients.